1. Field of the Invention
This invention relates to new derivatives of 4,5,6,7-tetrabromobenzimidazole and a method of their preparation.
2. Description of Related Art
An unsubstituted 2-amino-4,5,6,7-tetrabromobenzimidazole found in fruits as a product of degradation of the anthelmintic agent Benomyl (Pease and Gardiner, 1969), is known in the art. Its structure has been proposed on the basis of a mass spectral analysis. However, its synthesis has not yet been reported.
From US Patent Application Publication No. 2003/0027842A1 known are 2-hydroxy-4,5,6,7-tetrabromo-benzimidazole, obtained by bromination of 3-carboxy-4,6,7-tribromo-2-hydroxybenzimidazole, and 1-alkyl-4,5,6,7-tetrabromobenzimidazole, prepared by alkylation of 4,5,6,7-tetrabromobenzimidazole with alkyl halide in alkaline solution.
Halogeno derivatives of benzimidazole exhibit many interesting biological properties. It is known that derivatives of 2-trifluorobenzimidazole as well as some derivatives of bromobenzimidazoles have marked antiprotozoic, antibacterial and antiviral activity (Navarete-Vazquez et al. Bioorg. Med. Chem. Lett. 11, (2001), 187-191; Andrzejewska et al. Eur. J. Med. Chem. 37 (2002), 972-978). The most probable explanation for the considerable biological activity of halogeno derivatives of benzimidazole is their ability to interfere with cell metabolism by inhibition of enzymes that control the metabolism of protein kinases.
Protein kinases constitute a large superfamily of enzymes (more than 500 members encoded by the human genome) present in every eukaryotic and prokaryotic cell and playing a special role as regulators of cellular mechanisms. These enzymes catalyze the transfer of phosphate group from ATP or GTP to amino acids, i.e., serine, threonine or tyrosine. These are in general “quiet” enzymes, which activate themselves at individual stages of cell metabolism, including pathological stages. At present, protein kinases and particularly their inhibitors arouse the interest of researchers as potential objects that would help in the design of specific drugs. For example, Gleevec, a drug for treating chronic myeloid leukemia is a result of studies on kinase inhibitors (Druker B. J., Talpaz M., Resta D. J., Peng B., Buchdunger E., Ford J. M., Lydon Nn. B., Kantarjian H., Capdeville R., Ohno-Jones S., Sawyers C. L. N. Eng. J. Med. 344, (2001) 1031-1037).
A special family of protein kinases are the so-called casein kinases (CK1 and CK2), for which more than three hundred proteins—substrates for these enzymes—exist. They participate in many cell processes (Litchfield D. W. Biochem. J. 369, (2003) 1-15). There are many facts indicating that their subunits can act as oncogenes (Kelliher M. A., Seldin D. C., Leder P. EMBO J. 15, (1996) 5160-5166; Orlandini M., Semplici F., Feruzzi R., Meggio F., Pinna L. A., Oliviero S. J. Biol. Chem. 273, (1998) 21291-21297; Landesman-Bollag E., Channavajhala P. L., Cardiff R. D., Seldin D. C. Oncogene 16 (1998) 2965-2974). The most widely known and potent inhibitor of casein kinase 2 (CK2) is 4,5,6,7-tetrabromobenzotriazole (TBB) (Sarno et al., 2001).